NK cell exhaustion in melanoma

ADAM FARKAS & KEERTHI SADANALA

NK cells are a type of lymphocyte that are key participants in the innate immune response to tumorigenesis, equipped to respond rapidly through induction of cytokines and deployment of cytotoxic activity. It is thought that NK cells contribute to containing tumor growth, as NK cell infiltration in tumor tissue correlates with better prognosis whereas reduced activity of peripheral blood NK cells is associated with an increased risk of cancer.

Our lab has found evidence that NK cells progressively undergo a process of “exhaustion” from early to late stage melanoma, a state characterized by a failure to proliferate, to produce the pro-inflammatory cytokine interferon gamma (IFNγ) or to kill target cells. In particular we demonstrated for the first time that Tim-3, a checkpoint inhibitory receptor, is over-expressed in exhausted NK cells from advanced melanoma patients, and that its blockade reverses this exhausted phenotype and improves NK cell function. Most strikingly, however, we have recently found that patients who have a clinical response to ipilimumab treatment spontaneously restore their NK cell function, despite the fact that these cells express little or no CTLA-4 (or PD-1 or PDL-1). We hypothesize that reversal of the NK cell exhaustion state using checkpoint blockade immunotherapy treatments will contribute towards the full restoration of immune responses that are required to eliminate melanoma cells.

Elena & Adam are interested in characterizing NK cell dysfunction in melanoma and in determining the intracellular signals involved in restoring NK cell activity. In parallel, we are also studying NK cell exhaustion in different melanoma mouse models, which will allow us to try different combinations of monoclonal antibodies against checkpoint molecules or targeted therapies not designed yet for human use. In addition, we aim to determine at which point during melanoma progression restoration of NK cell activity is most effective in reducing tumor progression. We will also determine if intratumoral and/or systemic administration of the therapy will have same effect on anti-tumor responses.